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Abstract The present study was designed to examine whether cetrorelix as GnRH-ant has potential protective effect aganist ɤ-radiation-induced ovarian dysfunction in vivo by studying its effects on folliculogenesis, different markers of OS, proliferation, apoptosis, and angiogenesis in an experimental model of ɤ-radiation-induced ovarian failure in rats. The study was designed as follows: Animals (total no.=100) were divided randomly into four groups (group=25) and were either exposed to a single dose of ɤ-radiation (3.2 Gy) and/or treated with cetrorelix s.c. (0.5 mg/kg) once daily for ten days. The following parameters were investigated: A. Assessment of serum AMH, E2, and FSH level. B. Morphometric analysis of ovarian follicles type and number. C. Histopathological examination: H&E used for routine histological examination of ovarian tissues. D. Assessment of OS markers: ovarian content of GSH and MDA, in addition to GPx and GRx activities. E. Assessment of Apoptotic markers: ovarian expressions of cytochrome c and caspase 3 and BAX/BCL-2 ratio. F. Assessment of proliferative marker (PCNA). G. Assessment of Angiogensis: ovarian VEGF expression. Summary and conclusion 105 The results of the present study can be summarized as follows: 1. The current study demonstrated that endocrine environment was affected by radiation, as shown by a drastic increase in FSH levels and a significant decrease in AMH and E2 levels. Additionally, as a result of the early depletion of primordial follicles, irradiated females displayed POF. On the other hand, treatment of female rats with cetrorelix corrected the change in AMH, E2, and FSH levels caused by radiation. 2. The number of primordial follicles may have reached such a critical value that the mechanisms controlling recruitment of primordial follicles into the growing pool could not be effective in the irradiated ovaries. As a result, we have demonstrated that whole-body irradiation with a single dose of 3.2 Gy induced a depletion of the growing preantral follicles within a time period of 24 h, with marked reduction in GCs proliferation. In contrast, cetrorelix pre-treatment of the irradiated rats for 10 days preserved ovarian follicles’ stock and increased PCNA expression of the irradiated ovaries. 3. Histopathological examination using H&E stain showed that the stromal tissue of the irradiated ovaries occupied most of the ovarian structure which was characterized by severe hemorrhage with very few primordial follicles were detected at the periphery of the ovary. Curiously, treatment of rats with cetrorelix preserved ovarian tissues from radiation-induced hemorrhage and degeneration. 4. Regarding the OS, radiation exposure resulted in a significant increase in ovarian MDA accompanied with a significant depletion of GSH levels as well as GPx and GRx. activities. However, cetrorelix Summary and conclusion 106 treatment of the irradiated rats significantly reduced the radiationinduced production of ROS and inhibited subsequent lipid peroxidation marker (MDA). 5. Rats exposure to irradiation resulted in an increased ovarian and theca cells as well as ovarian epithelial cells apoptosis as evidenced by increased cytochrome c, caspase 3 expression, BAX/BCL-2 ratio. 6. Cetrorelix treatment for ten days of the whole body irradiated rats significantly diminished such apoptosis-induced. 7. Rats exposure to irradiation resulted in an increased angiogenesis (VEGF). However; cetrorelix treatment of the irradiated rats significantly reduced the radiation-induced production of VEGF. Summary and conclusion 107 Conclusions: Together, these findings support the conclusion that “Cetrorelix may elicit a protective effect against radiation-induced ovarian damage.” Cetrorelix stimulates in vivo folliculogenesis through increasing GCs proliferation, AMH, and E2 secretions, as well as GPx and GRx. activity, while decreasing FSH, lipid peroxidation and OS. Subsequently, cetrorelix treatment inhibits apoptosis through decreasing the expressions of cytochrome c, caspase 3, and BAX/BCL-2 ratio. Moreover, cetrorelix decreased angiogenesis measured marker; VEGF. All of these results provide an evidence of “The protective role of cetrorelix against IR-induced ovarian damage.” |